Binding, topoisomerase II leads to DSB

Certain TopoII poisons stabilize the intermediate cleavage complex and prevent the religation with appropriate DNA strands. Covalently DNA end-bound TopoII protein is digested and a hanging end is created. The same process happens in the translocation partner gene. Hanging ends of both genes are processed and subsequently joined by non-homologous end joining (Cowell and Austin 2012). Indeed, compounds that increase the rate of DNA cleavage and decrease the rate of DNA religation by topo II enzyme are often referred to as Topo II "poisons" (Nitiss 2009).Topoisomerase poisons stabilize the normally transient topoisomerase-induced DSBs and are potent and widely used anticancer drugs (Cowell and Austin 2012). They interfer with the religation step in the topoisomerase II reaction cycle, leading to the accumulation of DNA DSBs. The inhibition of the religation step will result in the formation of an unusual type of DSB called a cleavage complex, in which the topoisomerase protein remains covalently coupled to the DNA (Cowell and Austin 2012).

DNA topoisomerases are ubiquitous enzymes, which control the integrity of double-stranded DNA. They are thus key enzymes at all levels of living organisms. The available evidence suggest that important differences in sensitivity to topoisomerase inhibition  might exist among different cell types, depending on the amount of proliferative burden, of the TopoII enzymes and on physiological repair processes. Mesodermal precursor or hematopoietic stem and progenitor cells (HSPCs) are rapidly dividing cells with a high content of TopoII and for these reasons they can be a sensitive target during a critical developmental window (Hernandez and Menendez 2016).  In addition, evidence from micronuclei assay studies conducted in untreated and chemical-treated foetuses and newborns show that both the baseline and chemically induced micronuclei frequencies are higher in the foetuses and infants than in adults (Udroiu et al 2016). This is possibly indicating a greater sensitivity to genotoxic insult during development which can be due to the higher proliferation rate and lower ability of DNA repair of the hematopoietic stem cells. However, the role that the different microenvironments (foetal liver, infant bone marrow and adult bone marrow) during ontogenesis can exert on cell sensitivity cannot be ruled out (Udroiu et al. 2016). The existence of relevant interspecies differences is unknown, but it cannot be ruled out presently.